The present invention relates to new piperidyl- or piperazinyl-substituted-1,2,3,4-tetrahydronaphthalene derivatives as (R)-enantiomers, (S)-enantiomers or racemates in the form of free base or pharmaceutically acceptable salts thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a selective effect at a subgroup of 5-hydroxy-tryptamine receptors, designated the h5-HT1B-receptor (previously called the 5-HTIDxcex2-receptor) in mammals including man.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
Different classes of piperazinyl substituted benzanilide derivatives as 5-HT1D antagonists are disclosed in inter alia EP 533266, EP 533267, EP 533268, GB 2273930 and WO 95/11243.
WO 94/13659 discloses an extremely broad class of fused benzo compounds having a para substituted piperidyl or piperazinyl radical in the aromatic ring, said class of compounds are stated to bind to the 5-HT1A receptor.
WO 94/21619 discloses fully aromatic naphthalene ring system which may be substituted with a piperidyl or piperazinyl group, said compounds are also stated to be potent serotonin (5HT1) agonists and antagonists.
EP 402923 discloses 2-aminoalkyl or alkylenaromatic substituted 1,2,3,4-tetrahydronaphthalene derivatives having a further nitrogen substitution in the 5 position in the tetraline ring, said compounds act as dopamine agonists.
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine(5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients. The invention concerns compounds which have an effect on 5-HT neurotransmission.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The various effects of 5-HT may be related to the fact that serotonergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, xcex2-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 with the 5-HT1 receptor further divided into the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
The release of 5-HT at the nerve terminals is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT1A autoreceptors are located on the cell bodies in the raphe nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reducing the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the h5-HT1B receptors (in rodents the r5-HT1B receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses which has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal h5-HT1B autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. It would thus produce an antidepressant effect making it useful as a medication for depression.
Other vocalizations of h5-HT1B receptor subtype also exist. A large part of these postsynaptic receptors appear to be located on nerve terminals of other neuronal systems (so called-heteroreceptors). Since the h5-HT1B receptor mediates inhibitory responses an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having h5-HT1B activity may according to well known and recognised pharmacological tests be divided into full agonists, partial agonists and antagonists.
The object of the present invention is to provide compounds having a selective effect at the h5-HT1B receptor, preferably antagonistic properties, as well as having a good bioavailability. The effect on the other receptors chosen from, for example, the 5-HT1A, 5-HT2A, D1, D2A, D3, xcex11 and xcex12 receptor has been investigated. Accordingly, the present invention provides compounds of the formula I 
wherein
X is N or CH;
Y is NR2CH2, CH2xe2x80x94NR2, NR2xe2x80x94CO, COxe2x80x94NR2 or NR2SO2 
wherein R2 is H or C1-C6 alkyl;
R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl,
wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S and which may be mono- or di-substituted with R4 and/or R5;
wherein R4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C1-C6 alkoxy, NR6R7, OCF3, SO3CH3, SO3CF3, SO2NR6R7, phenyl, phenyl-C1-C6 alkyl, phenoxy, C1-C6 alkyl phenyl, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenylxe2x80x94C1-C6 alkyl, an optionally substituted heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl, or COR8;
wherein R6 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R7 is H, C1-C6 alkyl or C3-C6 cycloalkyl; and
R8 is C1-C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2;
wherein R5 is H, OH, CF3, OCF3, halogen, C1-C6 alkyl or C1-C6 alkoxy;
n is 0-4;
R9 is C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) C1-C6 alkyl; or COR8; wherein R6, R7 and R8 are as defined above,
as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof which possess a high selective effect at the h5-HT1B receptor and also shows sufficient bioavailability after oral administration.
In the present context C1-C6 alkyl may be straight or branched. C1-C6 alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl
In the present context C1-C6 alkoxy may be straight or branched. C1-C6 alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy.
In the present context C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In the present context halogen may be fluoro, chloro, bromo or iodo.
In the present context the heteroaromatic ring containing one or two heteroatoms selected from N, O and S preferably is a 5- or 6-membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring can be either substituted or unsubstituted.
In the present context the heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 may optionally contain a carbonyl function and is preferably a 5-, 6- or 7-membered heterocyclic ring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.
A preferred embodiment of the invention relates to compounds of formula I wherein Y is NHCO or CONH i.e. amides. Of those compounds, the compounds wherein R9 is C1-C6 alkyl, C1-C6 alkoxy, OCHF2 or OCH2F and R3 is unsubstituted phenyl, or mono- or di-substituted phenyl, and especially ortho-, meta- or para- substituted phenyl, and particularly those wherein the substituent R4 is phenyl, phenyl-C1-C6 alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF3, 4-piperidon-1-yl, n-butoxy or COR8 wherein R8 is phenyl, cyclohexyl, 4-piperidon-1-yl, 1-piperazinyl, morpholino, CF3, piperidino or NR6R7, are preferred.
Examples of Combinations of Substituents are:
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2is H, R3is(CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2is H, R3is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is cyclohexyl, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is CH3, C2H5 or C3H7.
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2is H, R3is phenyl, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is cyclohexyl, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is COR8, R8 is NR6R7, R6R7CH3, C2H5 or C3H7, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is OCH3.
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is COR8, R8 is NR6R7, R6R7CH3, C2H5 or C3H7, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2Hs or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2Hs or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R5 is CH3, C2H5 or C3H7;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R9 is CH3, C2H5 or C3H7;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2 phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7.
Preferred Compounds are:
(R)-N-[5-Methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;
(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide;
(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;
(R)-N-[5-Bromo-8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;
(R)-N-[5-Hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-butoxybenzamide;
(R)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;
(R)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide;
(R)-N-[5-Methyl-8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;
(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide;
N-(4-Morpholinophenyl)--(4-methylpiperazinyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide;
N-(Morpholinocarbonylphenyl)-8-(4-methylpiperazin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide;
(R)-N-[5-Ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide;
(R)-N-[5-Ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-(4-morpholinocarbonyl)benzamide;
(R)-N-[5-Difluoromethoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide; and
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide.
The compounds of the present invention are in the form of the racemate or the (R)- or (S)-enantiomer in the form of a free base or a pharmaceutically acceptable salt or solvate thereof. Compounds in the forn of the (R)-enantiomer are preferred ones. Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, fornic, hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic, sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These salts are readily prepared by methods known in the art.
The preferred solvates of the compounds of this invention are the hydrates.
In a second aspect the present invention provides a pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of formula I as an enantiomer or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof, optionally in association with diluents, excipients or inert carriers.
According to the present invention the compound of the invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical formulations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical formulations containing the compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or poly-vinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to the person skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or poly-ethylene glycol. Hardgelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into is hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.1% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may con tain colouring agents, flavouring agents, saccharine and carboxymethyl-cellulose as a thickening agent or other excipients known to the person skilled in the art.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.1% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
Suitable daily doses of the compound of the invention in therapeutical treatment of humans are about 0.01-100 mg/kg bodyweight at peroral administration and 0.001-100 mg/kg bodyweight at parenteral administration.
The compound of the invention may be used in a combination with a 5-HT reuptake inhibitor, such as fluoxetine, paroxetine, citalopram, clomipramine, sertraline, alaproclate or fluvoxamin, preferably paroxetine or citalopram. Another possible combination is to use the compound of the invention together with a monoamine oxidase inhibitor, such as moclobemide, tranylcypramine, brofaromide or phenelzine, preferably moclobemide or phenelzine . Still another possible combination is the compound of the invention together with a 5-HT1A antagonist, such as the compounds disclosed in WO 96/33710, preferably (R)-5-carbamoyl-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran.
In a further aspect the present invention provides the use of the compounds of formula I in therapy as a h5-HTIB antagonists, partial agonists or full agonists, preferably as antagonists and the use in the treatment of 5-hydroxytryptamine mediated disorders. Examples of such disorders are disorders in the CNS such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder),anxiety disorders (obsessive compulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, posttraumatic stress disorder), personality disorders (disorders of impulse control, trichotellomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders (age associated memory impairment, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson""s disease, thermoregulation, pain, hypertension. Other examples of hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and growth control of tumors (e g lung carcinoma).
The present invention also relates to processes for preparing the compound of formula I. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d T. W. Greene, Wiley-Interscience, New York, 1991.
1. In the case where Y is NR2CO and X is N
(i) Benzylation of the compound of the formula II, either as a racemate or as an enantiomer, 
to obtain a compound of formula III may be carried out by reaction with a suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate. The reaction may be carried out using a salt or the base of compound II in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst e.g. potassium iodide or sodium iodide, may increase the speed of the reaction. The nitrogen in compound II may also be protected by reductive alkylation with an arylaldehyde in the presence of a reductive agent such as sodium cyanoborohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine/enamine, and adjustment of pH to slightly acidic by an appropriate acid such as acetic acid may speed up the reaction, resulting in compound III.
(ii) Demethylation of the compound of formula III 
to obtain a compound of formula IV may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C.
(iii) Conversion of the compound of formula IV to a compound of formula V 
may be carried out by the reaction with a compound of formula VI 
where X stands for a leaving group, e.g. a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and Ra and Rb are hydrogen or a lower alkyl group e.g. methyl. The process may be carried out with a salt of the compound of formula IV obtained by reaction with a base such as K2CO3, Na2CO3, KOH, NaOH, BuLi or NaH. The reaction may be conducted in a suitable solvent e.g. an aprotic solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
(iv) Rearrangement of a compound of formula V to a compound of formula VII 
may be carried out in a suitable solvent e.g. aprotic solvent such as N,N dimethylformamide, dioxane, 1,1,3,3-tetramethylurea, tetrahydrofuran or hexamethylphosphoric triamide with a suitable base e.g. K2CO3, KOH, potassium tert-butoxide or NaH at a temperature within the range of +20xc2x0 C. to +150xc2x0 C.
The presence of a cosolvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or hexamethylphosphoric triamide in appropriate concentration in the solvent may increase the speed of the reaction.
(v) Hydrolysis of a compound of formula VII to a compound VIII may be carried out under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent e.g. H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20xc2x0 C. and +100xc2x0 C. or under basic conditions using bases such as NaOH or KOH in a suitable solvent e.g. H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20xc2x0 C. and +100xc2x0 C.
(vi) Conversion of compound of formula VIII to a compound of formula IX 
may be carried out by
a) reaction with a compound of formula X 
where R1 is C1-C6 alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent e.g. an aprotic/anhydrous solvent such as tetrahydrofuran or N,N-dimethylformamide in the presence of coupling reagent such as N,Nxe2x80x2-carbonyldiimidazole and the reaction may occur between +20xc2x0 C. and +130xc2x0 C. The reaction is followed by the reduction of the imide with a suitable reducing agent e.g. LiAlH4 in a suitable solvent e.g. diethyl ether or tetrahydrofuran at a temperature between +20xc2x0 C. and reflux, or
b) by reaction with a compound of formula XI 
where X stands for a leaving group, e.g. a halogen such as chlorine or bromine or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R1 is H, C1-C6-alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent such as ethanol, buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base e.g. K2CO3, NaHCO3 or KOH and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
(vii) Compound of formula IX may also be prepared by benzylation of the compound of the formula LVIII, where Re is a halogen such as chlorine, bromine or iodine, either as a racemate or as an enantiomer, 
to obtain a compound of formula LIX by the reaction with a suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate. The reaction may be carried out using a salt or the base of compound LVIII in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst e.g. potassium iodide or sodium iodide may increase the speed of the reaction.
(viii) Conversion of the compound of formula LIX to a compound of formula IX, where R1 is Hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, may be carried out by reaction with a compound of formula XXII. 
The process may be carried out in a suitable solvent e.g. an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(0) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalene (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between +20xc2x0 C. and +150xc2x0 C., resulting in the compound of the formula IX.
The conversion of LIX to IX can also proceed via the tranformation of XXII to an aminostannane or aminoborane using agents such as (N,N-diethylamino)tributyltin or tris(dimethylamino)borane in a suitable solvent e.g an aprotic solvent such as benzene, toluene, dioxan, tetrahydrofuran or N,N-dimethylformamide and then using similar conditions as described in the above description, resulting in the compound of the formula IX.
(ix) Halogenation of the compound of formula IX, where R1 is hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, 
to obtain a compound of formula XII may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound IX in an appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without a suitable base e.g. alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature.
A compound of the formula XII may also be prepared by benzylation of a compound of the formula XVI to obtain a compound of formula XII by reaction with a suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150 xc2x0 C. The presence of a suitable catalyst e.g. potassium iodide or sodium iodide, may increase the speed of the reaction. 
(x) Conversion of the compound of formula XII to a compound of formula XIII, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl and R9 is C1-C6 alkyl, may be carried out by a metal-halogen exchange, in a appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithium or metal e.g. buthyllithium, lithium or magnesium turnings, followed by treatment with appropriate alkyl halide such as methyl iodide, ethyl bromide or propyl iodide and the reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature, followed by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or treatment with other electrophiles such as acetaldehyde or methyl chloroformate and a thereafter following suitable work-up. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature.
In the case where acetaldehyde is used as electrophile, the above reaction is followed by reduction of the benzyl alcohol and cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C.
In the case where methyl chloroformate is used as electrophile, the above reaction is followed by reduction of the methyl ester in a suitable solvent such as diethyl ether or tetrahydrofuran with an appropriate reductive agent such as lithium aluminum hydride and the reaction may occur between +20xc2x0 C. and reflux, followed by cleavage of the benzyl groups and reduction of the benzyl alcohol by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C.
When R1 is hydrogen, the piperazine nitrogen is protected with a suitable protecting group before the lithiation step such as a benzyl group or another protecting group known by a person skilled in the art and then removed by methods known by a person skilled in the art, resulting in the compound of formula XIII.
(xi) Compound of formula XIII, where R1 is hydrogen, may also be prepared by, 
the conversion of the compound of formula LIX to a compound of formula LX, by the reaction with a compound of formula LXI, where Rc is a suitable protecting group such as a benzyl group. 
The process may be carried out in a suitable solvent e.g. an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(0) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalene (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between +20xc2x0 C. and +150xc2x0 C., resulting in the compound of the formula LX.
The conversion of LIX to LX can also proceed via the tranformation of LXI to an aminostannane or aminoborane using agents such as (N,N-diethylamino)tributyltin or tris(dimethylamino)borane in a suitable solvent e.g an aprotic solvent such as benzene, toluene, dioxan, tetrahydrofuran orN,N-dimethylformamide and then using similar conditions as described in the above description, resulting in the compound of the formula LX.
(xii) Halogenation of the compound of formula LX, 
to obtain a compound of formula LXII may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound LX in an appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without a suitable base e.g. alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature. 
(xiii) Conversion of the compound of formula LXII to a compound of formula XIII, where R1 is hydrogen and R9 is C1-C6 alkyl, may be carried out by a metal-halogen exchange, in a appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithium or metal e.g. buthyllithium, lithium or magnesium turnings, followed by treatment with appropriate alkyl halide such as methyl iodide, ethyl bromide orpropyl iodide and the reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature, followed by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or treatment with other electrophiles such as acetaldehyde or methyl chloroformate and a thereafter following suitable work-up. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature.
In the case where acetaldehyde is used as electrophile, the above reaction is followed by reduction of the benzyl alcohol and cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C.
In the case where methyl chloroformate is used as electrophile, the above reaction is followed by reduction of the methyl ester in a suitable solvent such as diethyl ether or tetrahydrofuran with an appropriate reductive agent such as lithium aluminum hydride and the reaction may occur between +20xc2x0 C. and reflux, followed by cleavage of the benzyl groups and reduction of the benzyl alcohol by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C.
(xiv) Conversion of a compound of formula XIII, where R1 is hydrogen, to a compound of formula XIV, 
where Rc is a suitable protecting group, may be carried out by the protection of the piperazine ring in a suitable solvent e.g. methylene chloride or chloroform with a appropriate protecting reagent e.g. di-tert-butyl dicarbonate with a suitable base e.g. triethylamine or K2CO3 and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C. 
(xv) Conversion of the compound of formula IX, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl to a compound of formula XV, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl may be carried out by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120.
(xvi) Halogenation of the compound of formula XV, where R1 is hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, 
to obtain a compound of formula XVI may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound XV in a appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without a suitable base e.g. alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature.
(xvii) Conversion of a compound of formula XVI, where R1 is hydrogen, to a compound of formula XVII, 
where Rc is a suitable protecting group, may be carried out by the protection of the piperazine ring in a suitable solvent e.g. methylene chloride or chloroform with an appropriate protecting reagent e.g. di-tert-butyl dicarbonate with a suitable base e.g. triethylamine or K2CO3 and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C.
(xviii) Halogenation of the compound of formula XVIII, where R9 is C1-C6 alkoxy, either as racemate or as an enantiomer 
to obtain a compound of formula XIX may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound XVIII in an appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without a suitable base e.g. alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature. 
(xix) Benzylation of the compound of the formula XIX, either as a racemate or as an enantiomer, to obtain a compound of the formula XX by reaction with a suitable benzylation agent e.g. benzyl halide such as benzyl bromide or benzyl chlorideor an activated alcohol e.g. benzylmesylate or -tosylate. The reaction may be carried out using the salt or the base of compound XIX in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base such as triethylamine, NaOH, NaHCO3 or K2CO3 at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst e.g. alkali metal halide such as potassium iodide or sodium iodide may increase the speed of the reaction. 
(xx) Conversion of the compound of formula XX to a compound of formula XXI, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl and R9 is C1-C6 alkoxy, may be carried out by the reaction with a compound of formula XXII, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl. 
The process may be carried out in a suitable solvent e.g. an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(O) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalen (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between +20xc2x0 C. and +150xc2x0 C.
(xxi) Conversion of the compound of formula XXI to a compound of formula XXIII 
where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl and R9 is C1-C6 alkoxy may be carried out by hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C.
(xxii) Conversion of compound of formula XXIII, where R1 is hydrogen, to a compound of formula XXIV, 
where Rc is a suitable protecting group, may be carried out by the protection of the piperazine ring in a suitable solvent e.g. methylene chloride or chloroform with a is appropriate protecting reagent e.g. di-tert-butyl dicarbonate with a suitable base e.g. triethylamine or K2CO3 and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C.
(xxiii) Dealkylation of the compound of formula XXI, 
to obtain a compound of formula XXV, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C.
(xxiv) Conversion of the compound of formula XXV to a compound of formula XXVI 
where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl may be carried out by hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C. 
(xxv) Conversion of the compound of the formula XII, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl, to a compound of the formula XXVII, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl, may be performed by a metal-halogen exchange, in a appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithiumor metal e.g. buthyllithium, lithium or magnesium turnings, followed by treatment with an appropriate electrophile such as bromomethyl methyl ether and a thereafter following suitable work-up. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(xxvi) Conversion of a compound of formula XXVII, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl, to a compound of formula XXVIII, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl, may be performed by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C. 
(xxvii) Alkylation of a compound of formula XXV, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl to obtain a compound of formula XXIX, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl may be carried out in a suitable solvent such as iso-propanol or dioxane with a suitable alkylating reagent such as chlorodifluoromethane in the presence of a suitable base such as NaOH or KOH at a reaction temperature between +20xc2x0 C. and +80xc2x0 C. 
(xxviii) Conversion of a compound of formula XXIX, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl, to a compound of formula XXX, where R1 is C1-C6-alkyl or C3-C6-cycloalkyl, may be performed by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C. 
(xxix) Conversion of a compound of formula XV, where R1 is C1-C6 alkyl or C3-C6 cykloalkyl to a compound of formula XXXI, where Y is NR2CO, R2 is hydrogen and R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5; may be carried out by acylation with an appropriate activated carboxylic acid such as an acid chloride in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkylamine such as triethylamine or by using a carboxylic acid (R3COOH) with an activating reagent e.g. N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C.
2. In the case where Y is CONR2 and X is N
(i) Nitration of a compound of formula XXXII, described in Johnson D. W.; Mander L. N. Aust. J. Chem. 1974, 27, 1277-1286, either as racemate or as an enantiomer, to obtain a compound of formula XXXIII, 
where Rd is C1-C6 alkyl, may be carried out by aromatic electrcphilic substitution using a suitable nitration reagent such as nitric acid or nitric acid and sulphuric acid in a suitable solvent e.g. acetic acid, acetic anhydride or water at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature.
(ii) Hydrolysis of a compound of formula XXXIII may be carried out under acidic conditions using acids such as H2SO4, HCl, HBr, in a suitable solvent such as H2O, ethanol, methanol, acetic acid or mixtures thereof and the reaction may occur at a temperature between +20xc2x0 C. and reflux or under basic conditions using bases such as NaOH or KOH in a suitable solvent such as H2O, ethanol, methanol or mixtures thereof and the reaction may occur at a temperature between +20xc2x0 C. and reflux, resulting in a compound of formula XXXIV 
(iii) Conversion of a compound of formula XXXIV to a compound of formula XXXV,where Y is CONR2, may be carried out by activation of the acid function of a compound of formula XXXIV as an acid halide such as an acid chloride with a suitable base such as a trialkylamine e.g. triethylamine or by using an activating reagent such as N,Nxe2x80x2-carbonyldiimidazole, N,N-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent e.g. methylene chloride, chloroform, toluene, N,N-dimethylformnamide, dioxane or tetrahydrofuran followed by the addition of an appropriate amine or aniline HNR2R3, where R2 is H or C1-C6 alkyl and R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5; and the reaction may occur between 0xc2x0 C. and +120xc2x0 C.
(iv) Conversion of the compound of formula XXXV to a compound of formula XXXVI, where Y is CONR2, R2 is H or C1-C6 alkyl and R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5; may be carried out by 
hydrogenation using a catalyst containing palladium, platina or nickel in a suitable solvent such as ethanol, methanol or acetic acid at a reaction temperature between +20xc2x0 C. and +120xc2x0 C.; or reduction with sodium dithionite in a suitable solvent.
3. In the case where X is CH and Y is NR2CO 
(i) The conversion of the compound of the formula XXXVII, where R9 is C1-C6 alkoxy, to the compound of the formula XXXVIII, where R1 is C1-C6 alkyl or C3-C6 cycloalkyl and R9 is C1-C6 alkoxy, may be performed by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithiumor metal e.g. butyllithium, lithium or magnesium turnings, followed by treatment with an appropriate N-alkylpiperidone, where alkyl (R1) is C1-C6 alkyl or C3-C6 cycloalkyl such as N-methyl-4-piperidone followed by a suitable work-up. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(ii) The compound of the formula XXXVIII may be reduced to the compound of the formula XXXIX by treatment with a suitable reducing agent such as sodium borohydride and a protonating agent such as CF3COOH, CF3SO3H or HCOOH in an appropriate solvent such as tetrahydrofuran or diethyl ether. The reaction may be performed at a reaction temperature between 0xc2x0 C. and reflux. 
(iii) Conversion of the compound of formula XXXIX to a compound of formula XL may be performed by hydrogenation using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C.
4. In the case where Y is NR2CO and R9 is in the 6-position
(i) Benzylation of the compound of the formula XLI, either as a racemate or as an enantiomer, 
to obtain a compound of formula XLII may be carried out by reaction with a suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate. The reaction may be carried out using a salt or the base of compound XLI in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst e.g. potassium iodide or sodium iodide, may increase the speed of the reaction.
(ii) Demethylation of the compound of formula XLII 
to obtain a compound of formula XLIII may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C. 
(iii) Conversion of the compound of formula XLIII to a compound of formula XLIV may be carried out with a compound such as trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride or carbon tetrachloride in the presence of a base such as 2,4,6-collidine, triethylamine or pyridine at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(iv) Conversion of the compound of formula XLIV to a compound of formula XLV where Rd is a C1-C6 alkyl group may be carried out in a suitable solvent such as dimethylsulphoxide or N,N-dimethylformamide with a suitable base such as a trialkylamine e.g. triethylamine in the presence of a suitable catalyst such as Pd(OAc)2 and a suitable ligand such as triphenylphosphine, 1,1xe2x80x2-bis(diphenylphosphino)ferrocene or 1,3-bis(diphenylphosphino)propane and a suitable.alcohol such as methanol, ethanol or propanol under a carbon monoxide atmosphere at a reaction temperature between 40xc2x0 C. and 120xc2x0 C. 
(v) Halogenation of the compound of formula XLV, where Rd is a C1-C6 alkyl group, to obtain a compound of formula XLVI may be carried out with a suitable halogenation reagent such as 1,3-dibromo-5,5-dimethylhydantoin. The reaction may be carried out using the salt or the base of the compound XLV in a appropriate solvent e.g. CF3SO3H or H2SO4 and at a reaction temperature between 30xc2x0 C. and 150xc2x0 C. 
(vi) Conversion of the compound of formula XLVI to a compound of formula XLVII, where R1 is C1-C6 alkyl or C3-C6 cycloalkyl may be carried out by the reaction with a compound of formula XXII, where R1 is C1-C6 alkyl or C3-C6 cycloalkyl. 
The process may be carried out in a suitable solvent e.g, an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(O) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalen (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between +20xc2x0 C. and +150xc2x0 C. 
(vii) Conversion of compound of formula XLVII to a compound of formula XLVIII may be carried out by the reduction of the alkyl ester in a suitable solvent such as diethyl ether or tetrahydrofuran with an appropriate reductive agent such as lithium aluminum hydride and the reaction may occur between +20xc2x0 C. and reflux, followed by cleavage of the benzyl groups and reduction of the benzyl alcohol by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C. Compound of formula XLVIII may also be prepared by,
(viii) Compound of formula XLVIII may also be prepared by protection of the amino group of the compound of the formula XVIII, either as a racemate or as an enantiomer, 
to obtain a compound of formula XLIX by the reaction with a suitable acylating agent e.g. trifluoroacetyl chloride or trifluoroacetic anhydride. The reaction may be carried out using a salt or the base of compound XVIII in a suitable solvent e.g. methylene chloride or chloroform with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of xe2x88x9220xc2x0 C. to +80xc2x0 C.
(ix) Nitration of a compound of formula XLIX 
to obtain a compound of formula L may be carried out by treating the compound with a suitable nitrating agent such as nitric acid in a suitable solvent such as acetic acid and the reaction may occur between 0xc2x0 C. and +30xc2x0 C. 
(x) Halogenation of the compound of formula L to obtain a compound of formula LI may be carried out with a suitable halogenation reagent such as N-bro mosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin. The reaction may be carried out in a appropriate solvent such as chloroform or methylene chloride with or without a suitable acid e.g. CF3SO3H or H2SO4 and at a reaction temper ature between 0xc2x0 C. and +80xc2x0 C. 
(xi) Conversion of a compound of formula LI to a compound of formula LII may be carried out by
a) hydrolysis of the amide in the compound of formula LI under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent e.g. H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20xc2x0 C. and +100xc2x0 C. or under basic conditions using bases such as NaOH or KOH in a suitable solvent e.g. H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20xc2x0 C. and +100xc2x0 C.
Hydrolysis is followed by
b) benzylation of the primary amine by reaction with a suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate. The reaction may be carried out in a suitable solvent e.g. N,N-dimethylformarnide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150xc2x0 C., resulting in the compound of formula LII. The presence of a suitable catalyst e.g. potassium iodide or sodium iodide, may increase the speed of the reaction.
(xii) Reduction of a compound of formula LII to obtain a compound of formula LIII may be carried out in a suitable solvent such as mixtures of methanol/water or ethanol/water in the presence of a suitable reducing agent e.g. sodium hydrosulfite at a reaction temperature between +20xc2x0 C. to +100xc2x0 C. 
(xiii) Conversion of compound of formula LIII to a compound of formula LIV 
may be carried out by the reaction with a compound of formula XI 
where X stands for a leaving group, e.g. a halogen such as chlorine or bromine or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R1 is C1-C6-alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent such as ethanol, buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base e.g. K2CO3, NaHCO3 or KOH and the reaction may occur between +20xc2x0 C. and +150xc2x0 C. 
(xiv) Conversion of the compound of formula LIV to a compound of formula LV, where R1 is C1-C6 alkyl or C3-C6 cycloalkyl and R9 is C1-C6 alkyl, may be carried out by a metal-halogen exchange, in a appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithium or metal e.g. buthyllithium, lithium or magnesium turnings, followed by treatment with appropriate alkyl halide such as methyl iodide, ethyl bromide or propyl iodide and the reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature or treatment with other electrophiles such as acetaldehyde or methyl chloroformate and a thereafter following suitable work-up. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature.
In the case where acetaldehyde is used as electrophile, the above reaction is followed by reduction of the benzyl alcohol by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C.
In the case where methyl chloroformate is used as electrophile, the above reaction is followed by reduction of the methyl ester in a suitable solvent such as diethyl ether or tetrahydrofuran with an appropriate reductive agent such as lithium aluminum hydride and the reaction may occur between +20xc2x0 C. and reflux, followed by reduction of the benzyl alcohol by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel, in a suitable solvent e.g. acetic acid or ethanol and the reaction may occur between +20xc2x0 C. and +120xc2x0 C. 
(xv) Demethylation of the compound of the formula LV to obtain a compound of formula LVI may be performed by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/acetic acid, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as C2H5Sxe2x88x92 or CH3C6H4Sxe2x88x92 in a suitable solvent. Suitable solvents may be acetic acid, methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C. 
(xvi) Conversion of the compound of formula LVI to a compound of formula LVII may be carried out by treatment with a compound such as trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride or carbon tetrachloride in the presence of a base such as 2,4,6-collidine, triethylamine or pyridine at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(xvii) Conversion of the compound of formula LVII to a compound of formula XLVIII may be performed by
a) treatment of compound of formula LVII with a suitable palladium catalyst such as palladium(II)acetate and a suitable ligand such as triphenylphosphine in the presence of a suitable acid e.g. formic acid in a suitable solvent such as N,N-dimethylformamide at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., followed by
b) reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux, resulting in the compound of formula XLVIII.
Another object of the invention is a process A(i), A(ii), B or C for the preparation of the compound of general formula I by
A(i)
acylation, in the case where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, Y is NR2CO, R2 is hydrogen and X, R3 and R9 are as defined in general formula I above with the exception of when R9 is a substituent that is susceptible to certain acylating agents, of a compound of formula A, 
with an activated carboxylic acid R3xe2x80x94COL where L is a leaving group or by using a carboxylic acid R3xe2x80x94COOH with an activating reagent.
Thus, the acylation according to the process A(i) may be carried out with an appropriate activated carboxylic acid, R3COL where R3 is as defined above and L is a leaving group, such as halogen e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkylamine such as triethylamine at a temperature between xe2x88x9220xc2x0 C. and reflux temperature or by using an carboxylic acid, R3COOH wherein R3 is as defined above with an activating reagent e.g. N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C.
A(ii)
acylation, in the case where R1 is hydrogen, Y is NR2CO, R2 is hydrogen, Rc is a protecting group and X, R3 and R9 are as defined in general formula I above with the exception of when R9 is a substituent that is susceptible to certain acylating agents, of a compound of formula B 
with an activated carboxylic acid R3xe2x80x94COL where L is a leaving group or by using a carboxylic acid R3xe2x80x94COOH with an activating reagent, followed by the removal of the protecting group Rc;
Thus, the acylation according to the process A(ii) may be carried out with an appropriate activated carboxylic acid, R3COL where R3 is as defined above and L is a leaving group, such as halogen e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkylamine such as triethylamine at a temperature between xe2x88x9220xc2x0 C. and reflux temperature or by using an carboxylic acid, R3COOH wherein R3 is as defined above with an activating reagent e.g. N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C., followed by removal of the protecting group Rc by hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between +20xc2x0 C. and +60xc2x0 C.
B
reacting, in the case where Y is CONR2, R2, R3 and R9 is as defined in general formula I above with the exception of when R9 is a substituent that is susceptible to certain alkylating reaoents XI, a compound of formula C 
with a compound of formula XI wherein X is a leaving group.
Thus, the reaction according to the process B may be carried out with a compound of formula XI wherein R1 is as defined in general formula I and X is a leaving group, e.g. a halogen such as chlorine or bromine or an alkane- or arenesulfonyloxy group such as p-toluene-sulfonyloxy group. The process may be carried out in a suitable solvent such as ethanol, butanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with or without a suitable base e.g. K2CO3, NaHCO3 or KOH and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
C
reacting, in the case where Y is NR2CO, R9 is halogen and Rl, R2 and R3 is as defined in general formula I above a compound of formula D 
with a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2.
Thus, the reaction according to the process C may be carried out by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound D in an appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without a suitable base e.g. alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature.
Another object of the invention is a compound having the formula 
wherein
X=N or CH;
Z=NH2 or COOH;
R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R9 is C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C1-C6 alkyl; or COR8; wherein
R6 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R7 is H, C1-C6 alkyl or C3-C6 cycloalkyl; and
R8 is C1-C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 wherein R6 and R7 are as defined above
and 
wherein
Y is CONR2 wherein R2 is H or C1-C6 alkyl.
R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5; wherein with R4, R5 and n are as defined above.
R9 is C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C1-C6 alkyl; or COR8; wherein R6, R7 and R8 are as defined above.